T regulatory type 1 (Tr1) cells were discovered in peripheral blood of severe combined immunodeficiency patients with long-term mixed chimerism after HLA-mismatched fetal liver hematopoietic stem cell transplant (HSCT) (Roncarolo et al., 1988, J Exp Med 167, 1523-1534; Bacchetta et al., 1994, J Exp Med 179, 493-502). Tr1 cells have strong immunosuppressive capacity in several immune-mediated diseases (Roncarolo and Battaglia, 2007, Nat Rev Immunol 7, 585-598; Roncarolo et al., 2011, Immunol Rev 241, 145-163; Pot et al., 2011, Semin Immunol 23, 202-208). The secretion of high levels of IL-10, and the killing of myeloid antigen-presenting cells (APCs) via Granzyme B are the main mechanisms of Tr1-mediated suppression (Groux et al., 1997, Nature 389, 737-742; Magnani et al., 2011 Eur J Immunol 41, 1652-1662). To date specific biomarkers for Tr1 cells have not been identified, limiting their study and clinical application. Tr1 cells are distinguished from T helper (TH)1, TH2, and TH17 cells by their unique cytokine profile and the regulatory function. Tr1 cells secrete higher levels of IL-10 than IL-4 and IL-17, the hallmark cytokines of TH2 and TH17 cells, respectively. Tr1 cells also secrete low levels of IL-2 and, depending on the local cytokine milieu, can produce variable levels of IFN-γ, together, the key TH1 cytokines (Roncarolo et al., 2011, Immunol Rev 241, 145-163). FOXP3 is not a biomarker for Tr1 cells since its expression is low and transient upon activation. IL-10-producing Tr1 cells express ICOS (Haringer et al., 2009, J Exp Med 206, 1009-1017) and PD-1 (Akdis et al., 2004, J Exp Med 199, 1567-1575), but these markers are not specific (Maynard et al., 2007, Nat Immunol 8, 931-941). CD49b, the α2 integrin subunit of the very-late-activation antigen (VLA)-2, has been proposed as a marker for IL-10-producing T cells (Charbonnier et al., 2006, J Immunol 177, 3806-3813); but it is also expressed by human TH17 cells (Boisvert et al., 2010, Eur J Immunol 40, 2710-2719). Moreover, murine CD49b+ T cells secrete IL-10 (Charbonnier et al., 2006, J Immunol 177, 3806-3813) but also pro-inflammatory cytokines (Kassiotis et al., 2006, J Immunol 177, 968-975). Lymphocyte activation gene-3 (LAG-3), a CD4 homolog that binds with high affinity to MHC class II molecules, is expressed by murine IL-10-producing CD4+ T cells (Okamura et al., 2009, Proc Natl Acad Sci USA 106, 13974-13979), but also by activated effector T cells (Workman and Vignali, 2005, J Immunol 174, 688-695; Bettini et al., 2011, J Immunol 187, 3493-3498; Bruniquel et al., 1998, Immunogenetics 48, 116-124; Lee et al., 2012, Nat Immunol 13, 991-999) and by FOXP3+ regulatory T cells (Tregs) (Camisaschi et al., 2010, J Immunol 184, 6545-6551). It was recently shown that human Tr1 cells express CD226 (DNAM-1), which is involved in the specific killing of myeloid APCs (Magnani et al., 2011 Eur J Immunol 41, 1652-1662). Overall, none of the abovementioned markers has been confirmed to be selective for Tr1 cells.
Tr1 cell-based clinical approaches are still largely limited by the inability to transfer a pure population of these cells. Moreover, a high frequency of Tr1 cells has been correlated with a positive outcome after HSCT (Bacchetta et al., 1994, J Exp Med 179, 493-502; Serafini et al., 2009, Haematologica 94, 1415-1426), but the absence of suitable markers has made the clinical screening of this type of Tr1 cells impossible. Hence, the availability of specific biomarkers of Tr1 cells would facilitate the transition of therapies targeting Tr1 cells from bench to bedside.
Thus, there is a need in the art for compositions and methods to identify and purify Tr1 cells. The present invention satisfies this unmet need.